PROJECT SUMMARY/ABSTRACT Despite significant research advances in the past two decades, Alzheimer?s disease (AD) remains the sixth leading cause of death that cannot be prevented, cured or even slowed. Attention has shifted towards under- standing early synaptic events in AD and related dementia (ADRD), resulting in memory deficits. However, the mechanism recruited and leading to synapse dysfunction associated memory deficits remains elusive thus im- peding successful therapeutic intervention. Bridging this critical gap in our current knowledge is the goal of this proposal. We present compelling preliminary results that support our hypothesis that inducible phospholipase D (PLD1) overexpression and the resulting aberrant signaling contributes to the progressive detrimental impact on synapses and subsequent cognitive deficits. We will test our central hypothesis by pursuing the following specific aims: (I) testing how elevated synaptic PLD1 levels/signaling contributes to synaptic dysfunction and memory deficits in ADRD; (II) evaluating the functional contribution of elevated PLD1 in preclinical mouse models and studying partners contributing to ADRD-like synaptic dysfunction and memory deficits. The present project is highly significant because the proposed studies will establish elevated PLD1 and the associated signaling part- ners as key players in promoting vulnerability causing progressive synaptic dysfunction and underlying cognitive deficits. The successful completion of the aims will provide insight into the involved molecular mechanisms and therapeutic possibilities using well-tolerated small molecule PLD1 inhibitor in preventing memory deficits asso- ciated with ADRD progression. The proposed project will improve our scientific understanding of how synaptic dysfunction is mediated by elevated PLD1 and interacting signaling partners in contributing to synaptic vulnera- bility.